title: Zederone, a sesquiterpene from Curcuma elata Roxb, is hepatotoxic in mice.
abstract: The present study aimed to investigate the hepatotoxicity of zederone isolated from Curcuma elata in mice. Adult male mice were intraperitoneally injected with a single dose of zederone (50-300 mg/kg body weight [BW]). Twenty-four hours after the injection, zederone induced liver enlargement with scattered white foci over the organ. The medium lethal dose (LD₅₀) value at 24 hours of zederone was approximately 223 mg/kg BW. Hepatic centrilobular necrosis with marked increases in plasma alanine transaminase activity and total bilirubin levels was observed. Zederone at a dose of 200 mg/kg BW markedly decreased the activity of superoxide dismutase and the hepatic glutathione content, whereas the activity of catalase was not altered. The compound at this dose also increased the messenger RNA (mRNA) expression of Cyp2b10 and Cyp3a11, which are the main drug-metabolizing enzymes in the liver. The mRNA expression of proinflammatory cytokine tumor necrosis factor α was increased. The nuclear factor-E2-related factor 2 protein, which is the transcription factor regulating the antioxidant gene expression, was decreased. The histopathology of massive hepatic centrilobular necrosis with an increase in the expression of cytochrome P450 (Cyp) suggests that the possible potentiation of zederone-induced hepatotoxicity implicated the induction of Cyps, which leads to the formation of biological reactive metabolites and that cause the oxidative stress and liver cell injuries.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand. Email: pawinee.pia@mahidol.ac.th.
authors.forename: Prapapan
authors.initials: P
authors.lastname: Pimkaew
authors.forename: Kanoknetr
authors.initials: K
authors.lastname: Suksen
authors.forename: Koravit
authors.initials: K
authors.lastname: Somkid
authors.forename: Ratchanaporn
authors.initials: R
authors.lastname: Chokchaisiri
authors.forename: Surawat
authors.initials: S
authors.lastname: Jariyawat
authors.forename: Aporn
authors.initials: A
authors.lastname: Chuncharunee
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D030024:Curcuma; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D027343:Rhizome; D012717:Sesquiterpenes / Q000633:toxicity*; D013250:Steroid Hydroxylases / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D000410:Alanine Transaminase; C586942:zederone
keywords: cytochrome P450; liver toxicity; sesquiterpene; zederone